Cationic Liposome-mediated Intravenous Gene Delivery

Liu, Yong; Liggitt, Denny; Zhong, Wendy; Tu, Guanhuan; Gaensler, Karin; Debs, Robert J.

doi:10.1074/jbc.270.42.24864

Cited by 227 publications

(125 citation statements)

References 31 publications

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“…41 This acquired response reduces the efficacy of repetitive administration of viral vectors. An advantage that cationic liposome-based lipoplexes possess over viral vectors is that they are less antigenic and therefore suitable for strategies requiring repeated injections 5,6,42 such as TAA therapy. Therefore, cationic liposome-based vectors or LPD might be effective in providing repeated boosts for specific tumor antigens since immunity would be raised against cells producing antigen, but not against the vector itself.…”

Section: Discussionmentioning

confidence: 99%

LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth

1999

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Our laboratory has recently developed a lipopolyplex response required assembly of DNA into a lipoplex or the consisting of DOTAP:cholesterol liposomes, protamine LPD lipopolyplex. Except for the heart, elevated levels of sulfate, and plasmid DNA (LPD) that provides improved cytokine were observed in all organs (lung, liver, kidney systemic gene delivery compared with lipoplex following and spleen) where LPD is known to have gene transfer tail vein injection in mice. Because endothelial cells are the activity. Methylation of immune-stimulatory CpG motifs in primary cells transfected in the lung, it was hypothesized the plasmid component of LPD inhibited the proinflammathat LPD might be an effective vector for gene therapy of tory cytokine response as well as the antitumor effect of pulmonary metastases. This hypothesis was examined by LPD in both tumor systems. This suggests that i.v. administesting the efficacy of cytokine (IL-12) and tumor suptration of LPD elicits a systemic proinflammatory cytokine pressor (p53) strategies for treatment of an experimental response that mediates the antitumor activity of the lipopomodel of pulmonary metastasis in C57Bl/6 mice. Surprislyplex. In addition, the antitumor activity was not observed ingly, all LPD complexes including those containing an in SCID mice suggesting a possible role for B or T lympho-'empty' plasmid provided a potent (Ͼ50% inhibition) and cytes in the antitumor response initiated by LPD. This repdose-dependent antitumor effect, compared with dextroseresents the first demonstration that an intravenously treated controls. In addition, i.v. injections of LPD containadministered cationic liposome-based nonviral vector can ing 'empty' plasmid also inhibited tumor growth in a subcutpromote a systemic, Th1-like innate immune response. aneous model of C3 fibrosarcomma. The antitumor effectThe immune adjuvant properties of LPD might prove to be correlated well with a strong and rapid proinflammatory suitable for delivering tumor-specific antigens in the context cytokine (TNF-␣, IL-12 and IFN-␥) response. Naked plasof DNA vaccination. mid DNA did not elicit a cytokine response and the

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Section: Discussionmentioning

confidence: 99%

LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth

1999

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“…Targeting DNA vectors to cellular Tf receptors has been tried successfully before by linking the ligand to polycation conjugates (Liu et al, 1995;Zhu et al, 1993), through association of the protein with cationic liposomes and by covalent coupling of anti-Tf receptor monoclonal antibodies to the distal ends of PEG on sterically stabilized liposomes (Shi et al, 2001) or on nanoparticles (Olivier et al, 2002). In this regard, we and others have demonstrated that the association of human Tf to cationic liposome/DNA complexes enhances transfection in a large variety of cells, including dividing and nondividing cells (Cheng, 1996;Simoes et al, 1998Simoes et al, , 1999b.…”

Section: Introductionmentioning

confidence: 99%

Improving lipoplex-mediated gene transfer into C6 glioma cells and primary neurons

Cruz

Simões

Lima

2004

Experimental Neurology

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The development of methodologies for gene transfer into the central nervous system is crucial for gene therapy of neurological disorders. In this study, different cationic liposome formulations were used to transfer DNA into C6 glioma cells and primary hippocampal and cortical neurons by varying the nature of the helper lipid (DOPE, Chol) or a mixture of DOPE and cholesterol (Chol) associated to DOTAP. In addition, the effect of the lipid/DNA (+/À) charge ratio, the association of the ligand transferrin to the lipoplexes, and the stage of differentiation of the primary cells on the levels of transfection activity, transfection efficiency, and duration of gene expression were evaluated. Mechanistic studies were also performed to investigate the route of delivery of the complexes into neurons. Our results indicate that DOTAP:Chol (1:1 mol ratio) was the best formulation to transfer a reporter gene into C6 glioma cells, primary hippocampal neurons, and primary cortical neurons. The use of transferrin-associated lipoplexes resulted in a significant enhancement of transfection activity, as compared to plain lipoplexes, which can be partially attributed to the promotion of their internalization mediated by transferrin. While for hippocampal neurons the levels of luciferase gene expression are very low, for primary cortical neurons the levels of transgene expression are high and relatively stable, although only 4% of the cells has been transfected. The stage of cell differentiation revealed to be critical to the levels of gene expression. Consistent with previous findings on the mechanisms of cell internalization, the experiments with inhibitors of the endocytotic pathway clearly indicate that transferrin-associated lipoplexes are internalized into primary neurons by endocytosis. Promising results were obtained in terms of the levels and duration of gene expression, particularly in cortical neurons when transfected with the Tfassociated lipoplexes, this finding suggesting the usefulness of these lipid-based carriers to deliver genes within the CNS. D 2004 Elsevier Inc. All rights reserved.

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“…39 Plasmid DNA was prepared by the modified alkaline lysis procedure, followed by polyethylene glycol precipitation, as described previously. 40 Preparation of LDC Sterile 10 mM solutions of the cationic liposome DOTIM octadecenoyloxy(ethyl-2-heptadecenyl-3-hydroxyethyl) imidazolinium chloride and cholesterol were prepared in a 1:1 molar ratio as described previously, except that the liposomes were extruded through a final filter diameter of 200 nm rather than 100 nm. 41 LDC were formed just before injection by gently mixing cationic liposomes with plasmid DNA at a ratio of 16 nmol lipid per 1 mg DNA in 5% dextrose in water at room temperature.…”

Section: Plasmidsmentioning

confidence: 99%

Vaccination with liposome–DNA complexes elicits enhanced antitumor immunity

2006

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Cationic liposomes have been shown to potentiate markedly the ability of plasmid DNA to activate innate immune responses. We reasoned therefore that liposome-DNA complexes (LDC) could be used to produce more effective plasmid DNA vaccines for cancer. To test this hypothesis, tumor-bearing mice were vaccinated with conventional plasmid DNA vaccines or with LDC vaccines encoding model tumor antigens and CD8 þ T-cell responses and antitumor activity were assessed. We found that although plasmid DNA vaccines generated large increases in antigen-specific CD8 þ T cells, they failed to elicit significant antitumor immunity. In contrast, LDC vaccines elicited large numbers of antigen-specific CD8 þ T cells and also generated significant antitumor activity against established tumors. The antitumor activity elicited by immunization with LDC vaccines was mediated primarily by CD8 þ T cells. Studies of the interaction of LDC with antigen-presenting cells found that LDC triggered dendritic cell production of interleukin-12 and interferon (IFN)-g production by natural killer cells in vivo. Activation by LDC was also accompanied by upregulation of costimulatory molecule expression. These findings suggest that by concurrently activating strong systemic innate immune responses and generating cytotoxic T-lymphocyte responses, LDC may be used to increase the effectiveness of therapeutic plasmid DNA vaccination for cancer.

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Cationic Liposome-mediated Intravenous Gene Delivery

Cited by 227 publications

References 31 publications

LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth

LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth

Improving lipoplex-mediated gene transfer into C6 glioma cells and primary neurons

Vaccination with liposome–DNA complexes elicits enhanced antitumor immunity

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